This collaborative project, between Emory University in the USA and the University of Cape Town (UCT) in South Africa, proposes to investigate biological mechanisms underlying the transgenerational effects of exposure to prenatal maternal psychological stress, anxiety, or depression. We propose to examine offspring gene expression as a potential contributor to this intergenerational association in this proposal. It has been suggested that a significant portion of fetal brain development occurs prenatally and this process may be influenced by maternal environment. Our recent work found that individuals with posttraumatic stress disorder (PTSD) and depression have reduced expression of DICER1 and selected downstream microRNAs (miRNAs). This stress-related DICER1/miRNA regulation pathway seems consistent in blood and brain in humans and mouse models. We hypothesize that this stress-related regulation pathway is also at play in young children being exposed to prenatal maternal PTSD and/or depression (PnM-PTSD/dep). We propose to extend our findings in the Drakenstein mother/child dyads through three aims. In Aim 1 we plan to compare DICER1 expression as well as genome-wide gene expression profiles between offspring cases (exposed to PnM-PTSD/dep) and offspring controls with no such exposure at birth. In Aim 2, we propose to examine genome-wide miRNA expression profiles between offspring cases and controls at birth. Through these aims, we hope to identify genes and pathways potentially implicated in the mechanisms underlying this intergenerational association. Through each of these aims, the proposal will build research capacity through training, site visits, collaborative data analyses, publications, and presentations. While the low-middle income (LMIC) site has some capacity in genomics research, it has very little capacity in the analysis of gene expression data; this grant will play a key role in building such capacity. Through collaboration between the LMIC and high-income investigators, we will lay the foundation - via infrastructure and collection of unique phenotypes and RNA data - for future studies of this unique mother-child cohort in the LMIC context.